1. Field of the Invention
The present invention relates to a class of proteins, and a method for treatment of autoimmune diseases, especially to the treatment of heretofore intractable diseases such as multiple sclerosis, myasthenia gravis, and rheumatoid arthritis through modulation of the immune system reaction. The composition is comprised of a modified anticholinergic alpha-neurotoxin.
2. Description of the Prior Art
Sanders et al. had commenced investigating the application of modified venoms to the treatment of Amyotrophic Lateral Sclerosis (ALS) in 1953 having employed poliomyelitis infection in monkeys as a model. Others antiviral studies had reported inhibition of pseudo rabies (a herpes virus) and Semliki Forest virus (alpha-virus). See Sanders' U.S. Pat. Nos. 3,888,977, 4,126,676, and 4,162,303. Sanders justified the pursuit of this line of research through reference to the studies of Lamb and Hunter (1904) though it is believed that the original idea was postulated by Haast. See Haast U.S. Pat. Nos. 4,341,762 and 4,741,902. The studies of Lamb and Hunter (Lancet 1:20, 1904) showed by histopathologic experiments with primates killed by neurotoxic Indian cobra venom that essentially all of the motor nerve cells in the central nervous system were involved by this venom. A basis of Sanders' invention was the discovery that such neurotropic snake venom, in an essentially non-toxic state, also could reach that same broad spectrum of motor nerve cells and block or interfere with invading pathogenic bacteria, viruses or proteins with potentially deleterious functions. Thus, the snake venom used in producing the composition was a neurotoxic venom, i.e. causing death through neuromuscular blockade. As the dosages of venom required to block the nerve cell receptors would have been far more than sufficient to quickly kill the patient, it was imperative that the venom was detoxified. The detoxified but undenatured venom was referred to as being neurotropic. The venom was preferably detoxified in the mildest and most gentle manner. While various detoxification procedures were known then to the art, such as treatment with formaldehyde, fluorescein dyes, ultraviolet light, ozone or heat, it was preferred that gentle oxygenation at relatively low temperatures be practiced, although the particular detoxification procedure was not defined as critical. Sanders employed a modified Boquet detoxification procedure using hydrogen peroxide (Boquet 1941), outlined below. The acceptability of any particular detoxification procedure was tested by the classical Semliki Forest virus test, as taught by Sanders, U.S. Pat. No. 4,162,303.
From 1972 to 1974, 113 patients were treated for ALS with the crude venom extract without reports of toxicity problems or other adverse reactions (Sanders, M. and Fellowes, 1975). The general cause of ALS has eluded scientists for decades though in a small proportion of that population it has been attributed to a defective cellular enzyme. The objective of the treatment was an attempt to decelerate, stabilize or possibly reverse the progression of the disease.
During that period, a product derived from oxidatively detoxified whole venoms (cobra and krait) was employed as a therapeutic agent in over 1,100 patients with ALS with the longest treated patients receiving treatment for over 12 years. The venom complex contained many potentially active components though the emphasis of research efforts have focused on the neurotoxic fraction. It is unknown what components of the venom were responsible for any benefits reported by Sanders. In patents issued to Haast, it was suggested that a combination of neurotoxins and an unknown component of viperid venom were required. (Sanders did not employ a viperid venom component). Haast employed native, unmodified venom fractions the administration of which was reported to cause quite extensive pain for 1-2 days post administration resulting often in short therapeutic periods even if the reported effects were quite dramatic.
The production of drug product by Dr. M. Sanders was achieved using hydrogen peroxide as the oxidizing agent in addition to other components giving rise to the recipe he employed for over 30 years (Sanders et al., 1975, 1978). This method was patented and published by Sanders on several occasions with the last patent expiring in 1994. Furthermore, several techniques have been developed for modifying neurotoxins. These have included hydrogen peroxide, ozone, performic acid, iodoacetamide and iodoacetic acid. Some of these procedures have been published and others patented. Obviously some procedures are easier than others to utilize and the focus for commercial production has been on the simpler methods.